The proposed research program will study the adverse effects of alcohol on cellular proliferation, maturation, protein synthesis and cell survival in relationship to the effect of alcohol on pyridoxine and folate metabolism. Using new techniques developed within this laboratory, a proven animal model and human protocol studies, specific mechanisms of alcohol toxicity on the availability, gut uptake, tissue uptake and storage, delivery and intracellular metabolism of folate and pyridoxine metabolites will be defined and characterized. In the area of diturbed folic acid metabolism the investigations will be directed at a number of the steps of the enterohepatic folate cycle and at the reported alcohol effect on the creation and subsequent release of folate storage forms within hepatic tissue. This is an outgrowth from previous investigations within the laboratory. In the area of pyridoxine metabolism new techniques will be applied to characterizing the levels and activities of essential kinase and oxidase enzymes within intracellular systems, pyridoxal-5-phosphate balance and the presence of evidence of tissue pyridoxine deficiency in alcoholic man. Moreover, parallel examples of drug induced and acquired mitochondrial abnormalities will be studied under detailed protocols to look for specific defects in the handling of pyridoxine and the responsiveness to therapeutic trials of pyridoxine metabolites.